J . Org. Chem., Vol. 44,'Vo. 9, 1979 1519
Synthesis of 9,1@-Dihydroanthracen-9,lO-imines
Synthesis of 9,10-Dihydroanthracen-9,lO-imines Paul S.Anderson, Marcia E. Christy, C. Dylion Colton, Wasyl Halczenko, Gerald S.Ponticello, and Kenneth L. Shepard* D e p a r t m e n t of Medicinal Chemistry, Merck S h a r p a n d Dohme Research Laboratories, W e s t Point, Pennsylvania 19486 Received S e p t e m b e r 22, 1978
The cycloaddition of benzynes with isoindoles to generate 9,10-dihydroanthracen-9,10-imines has been examined in detail. A versatile synthesis of these ring-strained heterocycles based on a detailed analysis of the 2,3-dihydro-1H-isoindol-1-one(phthalimidine) approach to the prerequisite isoindoles is presented. A variety of synthetic methods to phthalimidines were evaluated and developed including (1)reductive amination of o-acylbenzoic acids, ( 2 ) amidoalkylation of benzoic acids, (3) halogenation and amination of o -alkylbenzoic acids, and (4) reduction of phthalimides. In addition, generation of benzynes from chlorobenzenes and lithium tetramethylpiperidide greatly increases the scope of the Diels-Alder reaction to form the desired products. Cycloaddition of benzynes (1)t o isoindoles (2) constitutes
1
R' I
R' I R
R' 1
RZ
I
3
2
(eq 1)the only known synthetic route t o the 9,lO-dihydroanthracen-9,lO-imine ring system (3).l In view of the transient nature of benzyne and the chemical sensitivity of isoindoles,Z it is not surprising that among the few derivatives of this ring system which have been reported most are derived from the -~O stable 1,3-diphenylisoindoles (2, R' = R2 = C ~ H S ) . ~ Set forth here is a broader analysis of the Diels-Alder approach to these heterocyclic compounds which demonstrates that cycloaddition has considerable utility when the methods of benzyne and isoindole generation are appropriately selected and combined. Emphasis is placed on the use of readily available precursors for 1 and 2, the generation of 1 and 2 in a reaction medium compatible with subsequent cycloaddition, and the ability to prepare nuclear substituted derivatives of 3 in a n efficient manner such that mixtures of isomers are avoided when possible. These points are illustrated in detail below. In order to broaden the scope of the cycloaddition, conditions were needed such that the transient benzyne 1 could be efficiently generated in the presence of a chemically reactive isoindole. Furthermore, a method for generating the isoindole from an available intermediate so that storage and purification of this reactive species would be minimal also was desirable. We have found that the action of lithium tetramethylpiperidide o n chlorobenzenes as the source of benzyne (eq 2)11 coupled with conversion of phthalimidines to isoindoles on l l I
4
exposure to alkyllithium reagents (eq 3)"-15 provided the most efficient solution to these problems. Thus, substituted chlorobenzenes are readily available in comparison with the corresponding precursors needed for other benzyne generation methods, and phthalimidines are prepared easily from o alkylbenzoates (eq 4),16o-acylbenzoic acids (eq 51," m-haloand m-alkylbenzoic acids (eq 6),18and phthalimides (eq :).Ig
I Li
6
8
RNH,
a C O O H COR? 9
(51
NaBH,
0
s TscherniacEinhorn reaction
10
11
12
Furthermore, when isoindoles are prepared from phthalimidines via the alkyllithium route, the product is suitable for use in the cycloaddition reaction with only minimal workup and no further purification. The examples below illustrate and further elaborate these points as they relate to the scope of the cycloaddition method. I t should be noted that injudicious use or combination of the previously described methods in many situations would produce isomeric products as well as involve unnecessary svnthetic effort. Discussion
5
(3)
0022-3263/79/1944-1519$01.00/O
Since a major portion of the work described here required flexibility in the choice of R, R1, and R' in structure 2, and thus 3 (see Tables I-V), an important objective was to examine the scope of available isoindole syntheses in meeting this condition. Although a number of synthetic approaches to isoindoles have been described, few offer any degree of versatility for the substituents on the isoindole nucleus.'-'() Of these methods, only two, the a,crl-dibromo-o-xylene synthesis 1979 American Chemical Society
Anderson et al.
1520 J . Org. Chem.. Vol. 44, No. 9, 1979
Table I
R
I C. subs1i tuent(s) ____
mp,
yield,
isoindole method0
benzyne precursor
registry
2367-76-2
OC
%
la'
CH:]
1.3-di-F
151-153 dec
5
1,3,5-F3 2-Br
Ih
153 (grad)
14
B
1-Br 2-F
1.07 ( t , J = 67.47/67.87 6 Hz, 3 H) 2.07 (s, 3 H) 2.27 im, 2 H) 5.27 (s, 1 H)'j'
5,66/5.81
3.42/3.39
IIgd C2H.i
CH,j
132-134
15
B
1-Br 2-F
6 02/6.21
3.9913.94
IIh' CH3
CH:,
2,3-di- 153-155 C1
19
B
1-Br 2-F
1.03 (t, J = 71.78171.39 6 Hz, 3 H) 1.83 (s. 3 H) 2.33 im, 2 H) 5.4.5 (s, 1 HI" 1.92 (s, 3 H) 56.86/56.42 2.23 (s, 3 H) 5.53 (s, 1 H) 7.05-7.65 (m. 4 H) 7.62 (s, 1 HI 7.68 !s. 1 Hj"
3.9813.94
3.68/3.62
See corresponding footnotes in Table I. C1: calcd 9.54; obsd 9.34
addition to a phthalimidine.12-15 The N-substituted phthalimidines (13) are readily accessible from phthalic anhydride by conversion to phthalimides ( 12)21followed by reduction with zinc in acetic acidI5 (eq 7 ) .These products may also be prepared by the reductive amination of 2-carboxybenzaldehyde with the appropriate primary amine and sodium cyanoborohydride (eq 5, R2 = H)." In addition, these phthalimidines can be generated from methyl o-toluate by benzylic bromination (NBS) followed by condensation with the required amine as described by Danishefskyl'j (eq 4). The synthesis of compounds of this type having aromatic substituents significantly complicates the required methodology. In the simplest situation where two identical substituents are desired on the same aromatic ring in the 1 and 4 or 2 and 3 positions, isomeric products do not arise and the problem reduces to choosing whether the isoindole or the benzyne should be the source of these substituents. As indicated, we have carried out both synthetic routes to the di-
chloro product 27 to illustrate this principle. 4,5-Dichlorophthalic anhydride was converted to N-methyl-4,5-dichlorophthalimide and reduced with zinc and acetic acid to 24. Treatment with methyllithium generated 25, and condensation with benzyne (0-bromofluorobenzene, method G) gave 27. Preparation of 26 followed by cycloaddition with 4,5-dichlorobenzyne produced the same product (27). The most important criteria in the route to analogous products would be the availability of either intermediate. CHI
0
24
25
I' NCH, 26
+ 27
J . Org. Chem., Vol. 44, No. 9, 1979 1523
Synthesis of 9,10-Dihydroanthracen-9,lO-imines In the case of 9- or 10-substituted-9,lO-dihydroanthracen-9,lO-imineswith a single aromatic substituent, designing a scheme to avoid the synthesis of a mixture of isomeric products becomes the principal concern. As suggested earlier, the lack of selectivity in the cycloaddition required that the substituent be introduced via the isoindole. The phthalimidine route to the desired isoindoles is preferred since procedures can be chosen to provide pure substituted isoindoles as illustrated below for the synthesis of 2,9,11- and 3,9,ll-trimethyl-9,10-dihydroanthracen-9,lO-imines. The 2,9,11-trimethyl isomer (33) requires 2,6-dimethylphthalimidine (31) as the precursor to the generation of I ,2,6-trimethylisoindole (32). Amidoalkylation's (e.g., eq 6) of m-toluic acid (28) with N-(hydroxymethy1)phthalimide in sulfuric acid produced 6-methylphthalimidine (30) directly. Alkylation of the amide nitrogen (NaH, CHsI, DMF) gave the 2,6-dirnethylphthalimidine (31). Addition of methyllithium followed by condensation with benzyne produced the %,9,11-trimethylisomer (33). In contrast, 2,s-dimethyl-
mediates. Of these, the reductive amination procedure is superior in all respects. As an illustration, o-diethylbenzene (39) was dibrominated followed by treatment with methylhydrazine and hot aqueous base to give 1,2,3-trimethylisoindole (42,
0
COOH C'OCH
28
\CH
29 45
--+HN&'
+H
\
(1) MeOH. H*
'&NCH) \
( 2 ) NBS
30
46
acooc 2
CHBr
31 43
I CH 44
32
33
phthalimidine (36) is the necessary precursor for the 1,2,5trimethylisoindole (37) that is required for the 3,9,ll-trimethyl derivative (38). 4-Methylphthalic anhydride (34) was converted to 2,4-dimethylphthalimide (35), which, utilizing the principle of selective reductions of 4-substituted phthalimides,'* was reduced (Zn, HOAc) to the requisite phthalimidine (36). The 1,2,5-trimethylisoindole (37) was generated by addition of methyllithium, and cycloaddition with benzyne gave the 3,9,11-trimethylisomer (38).
35
34
+
&XC'H
HC'
\
d l H \
+
\
aCH
HC
37
36
-
26% yield). The same isoindole was prepared from o-ethylbenzoic acid (43) by conversion to the methyl ester, bromination (NBS), amination ( C H ~ N H Z )and , addition of methyllithium (76%).Using o-acetylbenzoic acid (46) in the reductive amination procedure followed by addition of methyllithium, the isoindole 42 was formed in better than 90% yield. Although all of these sequences provide the desired compound, the most accessible starting material is an acylbenzoic acid such as 46. These derivatives are readily available from the action of organocadmium reagents on phthalic anhydrides, and their use allows a broader versatility of the substituents in the isoindole (2). Thus, in a 1,2,3-trisubstituted isoindole, one substituent would derive from the organocadmium reagent, one from the amine employed in the reductive amination, and the third from the organolithium reagent used to convert the phthalimidine to the target isoindole. In those nuclear substituted anthracenimines where both bridgehead substituents are methyl, or other identical groups, the problem of isomeric synthesis is equivalent to those products that contain hydrogen a t these positions. Therefore, the choice of synthetic method depends upon whether a nuclear substituent could be introduced best via the isoindole or the benzyne. In general, the latter alternative usually is the better choice as described earlier. However, where the appropriate phthalic anhydride is available, nuclear substituents can be selectively introduced by method E. For example, 4-methylphthalic anhydride (34), when treated with dimethylcadmium, gives a mixture of acetyltoluic acids 47 and 48. Reductive amination with methylamine maintains a mixture of products at the phthalimidine stage (49 and 50), but addition of methyllithium generates a single isoindole (51). Condensation of this isoindole with benzyne produces a product (52) identical with that from 1,2,3-trimethylisoindole(42) and 4-methylbenzyne.
38
9,lO-Disubstituted Derivatives (Tables I11 and IV). In the synthesis of 9,lO-disubstituted derivatives, three methods (A, D, and E) were employed to synthesize isoindole inter-
Anderson et al.
1524 J . Org Chenz., Vol. 44, No. 9, 1979
uimpd Iflae
R
substituent(s)
mp,"C
169-172
CH3
%
isoindole method"
52,
A, D,
CI
yield,
benzyne precursor
registry no.
method *
E
1.80 (s, 6 H) 2.00 (s, 3 H)"
67 471
67.66
H, calcdl obsd 5.661
5.86 5.951 6.13
2-CHz
153dec
28
A
1-F 2-Br 4-CH3"
1.83 (s, 6 H) 2.07 (s, 3 H) 2.25 (s, 3 Hjw
68.071
CH3
2-c1
118-130
16
D, E
1-1 2-Br
1.97 (s, 6 H) 2.23 (s, 3 H)"
60.401 5,341 60.40 5.01
CH3
1-F
191-193
24
A
I I I h P CH3
IIlcfl
'H NMR, 6
12, calcdl obsd
68.43
N, calcdl obsd 3.441 3.36 3.311
3.18 3.711 3.67
4-CIP
IIId'
Iller
CH3
2-0CH.j
116-122 dec
A
1.93 (s, 3 H ) (5, 3 H) 2.20 (s, 3 H)U
66651
2-Br'
2.07
1-Br 2-1
2.00 (s, 6 H) 2.30 (s, 3 H) 3.70 (s, 3 H)W
6433,' 6.211 64.18 6.26
3.751
1.80 (s, 3 H) 2.03 (s, 3 Hi 2.07 (s, 3 H P
75691
5.981
6.36
5.191 5.33
1.97 (s, 3 H) 2.07 (s, 3 H) 2.27 (s, 3 H) 3.73 (s.3 H)"'
67 59,'
5.961 6 34
:3.94/ 3.96
1.80 (s, 6 H) 2.03 (s, 3 H) 2.27 (s, 3 HI'
6.3.361
5,781 ;7 7 7
3.84
1,3-F2
4-OCH3"
IIIf
CH3
1-C1
Illg'
CHj
I-OCH:,
IIlh
CH3
2-CH3, 6-F mix 2-CH1, 7-F
1
CH3
1,3-C12
9.5
168-169
17
D
l-OCH? 2x1
9
E
2-Br
2-Br
G
1,4-F2"
3.64
1
1-Br 2-F
G
1.83 (s. 6 H) 2.27 (s, 6 H) 3.53 (s, 2 H) 6.63 (s, 2 H)'
88.451 7.421 88.28 7.47
4.131 3.96
1,4-diCH:
101-10s base
15
1
I-Br 2-F
G
1.90 (s,6 H ) 2.10 (s, 3 H) 2.27 (s, 6 H) 6.53 (s, 2 HI?
8665,'
8.041 8.28
5.321 5.41
2-SCH3
108-114
5.5
D
1-SCHI 4-CI'
1.95 (s. 6 H) 2.23 (s, 3 H) 2.42 (s, 3 HIu'
61.67,'
5.951 6.02
:3.60/ 3.74
t58.:42/ 5.601 58.53 5.92
6.481 6.54
3.77,'
80 oc (0.1
33
D
2-S02N
178-180
5
D
(CHh
123-09-1
1-CH-
52944-34-0
(CHh 3- and
.574:30-24-7
H
H
]-CHI 2x1
196-199
1.8
E
2-CHO
120
15
D
62.07
1.3 (d,J = 6
H
1.93 (s. 6 H) 2.13 (s, 3 H) 2.57 (s. 6 HIu
1-CH3 2,6-C12
H
1.90 (s, 3 H) 2.10 (s, 3 H ) 2.20 (s, 3 Hj 2.40 (s, 3 H) 6.60 (s, 3 Hj 7 . 2 (m, 6 H)"
1-CH-
H
1.83 ( s ,6 HI 2.03 (s, 3 H) 2.03 (s, 3 HI 9.70 (s. 1 H),
64.681
F
2.0 ( m . 9 HIu
63 151 4.741 63.41 4.93
i3.881
H
1.87 (s, 3 HI 2.02 (s, 3 H )
52.071 3.951 52.01 4.01
2.891 2.77
1-SOzN(CHh
(OEth" 4-C1 2,3-di-F
182-184 dec
8
A
1-Br 2,4,5-F,jm
I &di-
120-125
11
E
1,3,5-C11
C1
87.09
Hz, 6 H ) 1.85(s. 3 H) 2.05 (s, :3 H) 2.10 (s, B HI?
4-Cll
llInd CHB
65.46
4.091 4.10
50
4-CI
CH?
67.89
5.62
153-155 base
1-CH-
IIlm'
,., s .,./ 2
5.30/
CH:.
1,J-di-
IIIj
D
98-100 base
66.75
108-70-3
(m. 6 H i u 7.03-7.50 2.13 (s, 3 Hi
64.68
5.70,'
6.08
3.63
3.68
J. Org. Chem., Vol. 4 4 , No. 9, 1979 1525
Synthesis of 9,10-Dihydroanthracen-9,lO-imines Table III(Continued) isoindole substicompd Illrc
R
tuent(si
CHS
1-CH:j
yield, mp, "C 184-185
V,
%
oda
benzyne precursor
19
A
l-CH,j 2-Br
meth-
dec
registry no.
method * G
?XI Ills#
[IIt'
CH?
2-CF3
CH3
2F
124-127
162 dec
4
10
A
A
I-CI 2-Br 4-CF,: 1 -Br
F
348-57-2 G
2,4-F2 IIlug
CHs
2-Br*
114- 134
20
4Bri
I-Br
F
35
D
133-137
I-Br
20
D
I-CI
27
E
2-Br
49
D
I-Br 2-F
iO.781 6.241 71 09 6.42
4.l?d
58.39i
.:3/4.70
6.3616 43
62.82/62.43
1.74/5.C19
7.3216.93
81.32/81.43 66.24/66.13
6.83/6.91
11.86/7.83
5.335.54
8.58/8.44
C,
2.07 (s, 3 H) 2.17 (s, 3 H) 2.60 (s, 3 H ) X
See the corresponding footnotes in Table I. * Registry no., 36953-42-1. O 0 Registry no., 626-55-1.
Chemistry of g,lO-Dihydroanthracen-9,lO-imines. AIthough most of the anthracen-9,10-imines reported here are listed. as salts, the majority are stable in both the salt and base forms. T o decide the usefulness of these products to further transformations, some investigations were made concerning
their chemical reactivity. The carboxaldehyde 54a could be converted to an oxime (54b) and dehydrated to the corresponding nitrile (54~). Thus, anthracenimines containing substituents not compatible with the benzyne generation step may be synthesized
1528 J . Org. Chem., Vol. 44, No. 9, 1979
Anderson e t al.
CH
tion salts. The hydrogen oxalate salt of 63 solvolyzed upon hot ethanol recrystallization to yield the dihydroanthracene derivative 64.3 Attempted recrystallization of the hydrogen oxalate salt of 65 from hot methanol resulted in solvolysiswith deamination to the 9,lO-dihydroanthracene 66. Both of these
I
CH! 54a, X = C H O b, X = CH=NOH c , X = CN
by subsequent transformation of a substituent which is compatible. In contrast to the oxidative instability of these compounds,24certain derivatives were capable of smooth catalytic reduction. Debenzylation of 55 to the amine 56 over
H,C'
64
I
CHj
(;H
CHI
55
56
CH, CH,
'NH(cH,),N(cH,),
.( COOH)2
H,C'
'OCH, 66
65
salts could be recrystallized from cold solvents with no decomposition.
CH, CH,
Summary
CH> C 58
S H CH, 57
59
Pd/C in acetic acid was accomplished, but the yield was low and unreproducible. However, the tetramethyl product 5725 was debenzylated in 9 i % yield (Pd/C, acetic acid, atmospheric pressure). The resulting secondary amine ( 5 8 ) could be converted to its N-ethyl derivative (59) in a reductive amination sequence with acetaldehyde (NaCNBH3). Thus, although our general synthetic approach to anthracenimines led only to tertiary amines, secondary amines can be derived subsequently from the N-benzyl compounds. The 3-hydroxypropyl analogue 60 was converted to the corresponding bromide 61
('H
CHI .CH-OH
\
-CH-Br
---t
\
/ I
CH
CH
61
60
/ CH 62
1
Rr63
(NBS, (C6Hs),P), and this product was treated with dimethylamine (in situ) to form the (dimethy1amino)propyl compound 63. This result illustrated that substituents which could not be carried through the isoindole synthesis step may be subsequently prepared from a group that is compatible with this step. The intermediate bromide underwent facile cyclization to The quaternary salt 62 on attempted isolation. In contrast to the marked stability of most of these products. two proved to be c.xceptionally labile as their acid addi-
It is thus apparent from the foregoing discussion that a are variety of substituted 9,10-dihydroanthracen-9,lO-imines readily available in reasonable yield (see Tables I-V). Except for oxidative instability, the products are stable and capable of further chemical transformations. As indicated earlier, the preparation of anthracenimines requires the synthesis of isoindoles in sufficient quantity and purity and a benzyne generation method compatible with the isoindole nucleus. We have examined the scope of the reaction whereby isoindoles can be generated for subsequent synthetic operations from phthalimidines. Phthalimidines are best prepared via the versatile reductive amination method from o-acylbenzoic acids, which allows introduction of a variety of N and potential bridgehead substituents. The generation of benzynes from chlorobenzenes and 3,4-pyridyne from 3bromopyridine using lithium tetramethylpiperidide and subsequent Diels-Alder addition with isoindoles establish the fact that substituted benzynes and pyridyne are more readily available for these types of reactions than heretofore believed. Experimental Section Essentially all reactions were run under dry nitrogen. 'H NMR spectra were run in the solvents indicated on a Varian A60A or T60 instrument, and chemical shifts (6) are measured from internal tetramethylsilane (Me&) as reference. Infrared spectra were recorded on a Perkin-Elmer Infracord. GLC analyses were determined on an F & M 810 flame ionization instrument. All melting points were taken in open capillaries (Thomas Hoover apparatus) and are uncorrected values. The synthesis of 9,10-dihydroanthracen-9,lO-imines is separated into two stages. Methods A-E depict the isoindole preparation, and methods F-H refer to the benzyne generation/Diels-Alder step. Preparation of Isoindoles. Method A. (All isoindoles in Table I were prepared by method A ) 1,2,3-Trimethylisoindole(2, R = R1 = R2 = CHI, X = H). A mixture of o-diethylbenzene (50 g, 0.374 mol), N-bromosuccinimide (146 g, 0.82 mol), benzoyl peroxide (0.1 g), and CC14 (800 mL) was heated under reflux with stirring and ultraviolet irradiation until the reaction was complete. The precipitated succinimide was filtered and washed with CC14, and the filtrate was concentrated to dryness. T h e residual oil was dissolved in absolute Et20 (800 mL). To the stirred solution under N2 was added, dropwise, a solution of methylhydrazine (40 g, 0.87 mol) in Et20 (50 mL). After stirring for 3 h a n d standing overnight, t h e Et& was decanted from the precipitated solid. The residue was dissolved in H20 (625 mL) and treated with 40% NaOH solution (375 mL), and the mixture was stirred at reflux for 1.5 h. After being cooled, the precipitate of crude
Synthesis of 9,10-Dihydroanthracen-9,lO-imines product was collected, washed with H20, and dissolved in Et20 (600 mL). T h e Et20 solution was washed repeatedly with HzO and dried over MgS04 with stirring and cooling in a n ice bath. T h e filtered solution was evaporated under reduced pressure, and the residual solid was triturated with petroleum ether, filtered, and dried in vacuo to yield 15.6 g (26%) of 1,2,3-trimethylisoindole. 5-Bromo-2-methylisoindole (2,R = CH3, R1= RZ = H , X = 5Br). Step A. 4,cu,a-Tribromo-o-xylene (14,R = R 1= Br, X = 4Br). Bromine (180 g, 1.15 mol) was added dropwise with stirring under ultraviolet irradiation at 125 "C to 4-bromo-o-xylene (92.5 g, 0.5 mol). After the addition was complete, the mixture was heated for 1h a t 125 "C and distilled to give 151 g (87%) of 4,a,a-tribromo-o-xylene, bp 130-145 "C (0.3 mm). Step B.T o a solution of 4,a,a-tribromo-o-xylene (151 g, 0.44 mol) in Et20 (900 mL) was added dropwise methylhydrazine (60 g, 1.3 mol) over a period of 4 h at room temperature. After stirring overnight, a 40% NaOH solution (800 mL) was added with stirring. T h e Et20 was removed by distillation, and H20 (800 mL) was added to the resulting suspension. The solution was refluxed for 3 h, cooled, and extracted with CHC13 (3 X 300 mL). The combined extracts were dried over Na2S04, filtered, and concentrated to dryness. The residue was distilled to give 30 g (33%): bp 126-128 "C (0.3 mm); 'H NMR (CDC13) t i 3.60 I,s, 3 H , NCH3). 5-Fluoro-2-methylisoindole (19): 28%; bp 90-100 "C (1mm); mp 60-65 'C. 5-Chloro-2-methylisoindole (2,R = CH3, R' = R2 = H, X = 5C1). 1,3-Diethyl-2-methylisoindole (2,R = CH3, R L= R2 = C2H5, x = H ) was prepared from o - d i - n - p r ~ p y l b e n z e n using e ~ ~ the procedure outlined for 1,2,3-trimethylisoindole: 23%; oil. 5-Bromo-1,2,3-trimethylisoindole (2,R = R L= R2= CH3, X = 5-Br): 35%; solid: 'H NMR ICDC13) d 2.43 (s, 6 H, ArCH?), 3.63 (s, 3 H , NCH3). 2-Methylisoindolefi (2,R = CH3, R' = RZ= X = H ) was prepared from o-xylene: 81%; waxy solid. Methods B, C, I),and E utilize the addition of an organolithium reagent to a phthalimidine for generation of the isoindole. The various methods thus reflect alternate procedures for preparation of the requisite phthalimidine. All of the new phthalimidines are listed prior to the listing of the isoindoles. Although only one method may be described for a specific isoindole, when it may be prepared by method E, that is the method of choice. Method B (Table 11). 2-Methylphthalimidine(13,R = CH3, X = H). Phthalic anhydride (40 g) and methylamine hydrochloride (40 g) were added to glacial AcOH (750 mL) and stirred for 5 min. Sodium acetate (anhydrous, 48.6 g) and additional AcOH (250 mL) were added, and the mixture was heated t.o reflux for 2 h. The hot mixture was filtered and t h e filtrate was cooled to 70 "C. Zinc dust (95 g) was added rapidly with stirring, and the resulting mixture was heated to reflux for a n additional 4 h. The mixture was filtered while hot, and most of the solvent was removed in vacuo. Saturated NaHCO:1 solution (700 mL) was added cautiously to the milky residue. The resulting mixture was extracted with CHC13 (4 X 200 mL). T h e combined extracts were washed with saturated NaHC03 solution, HzO, and saturated NaCl solution and dried (MgS04). Removal of the CHC13 in vacuo gave 35.3 g of an off-white solid, mp 102-112 "C. Recrystallization from cyclohexane gave material with mp 112-115 "C (lit.I9mp 114.;7--115"C). 2-Benzylphthalimidine (13, R = CHzCsHs, X = H): using phthalic anhydride and benzylamine hydrochloride; m p 88-90 "C (ligroine) (lit." m p 89-90 "C). 2-Ethylphthalimidine(13,R = C2H5, X = H): from phthalic anhydride and ethylamine hydrochloride as above; bp 88-91 "Ci0.07 mm (lit.28mp 45 "C). 2,5-Dimethylphthalimidine(36):from 4-methylphthalic anhydride and methylamine hydrochloride as above; m p 38-47 "C; 'H NMR (CDClZ) d 2 33 ( s , 3 H,ArCH3),3.1 (s,3H,NCH8).4.23 (s,2 H , -CH?N CHCH,), 1.8 (m, 2 H , -CHzCHs), 3.15 (m, 1 H, NCH2-),3.8 (m, 1 H, NCH2-),4.5 ( q , J = 7 H z , l H , >CHCH3),7.4 im, 3 H , aromatic). 7.75 (m, 1 H , aromatic). 2-Butyl-3-methylphthalimidine: 79%; bp 109-114 "C (0.1 mm); GLC homogeneous; 'H NMR (CDC13) 6 1.35 (m, 7 H , -CH&HzCH3), 1.4 (d. J = 6 Hz. 3 H. >CHCH3), 3.3 (m, 1 H, NCHz), 4.0 (m, 1 H , NCH?), 4.6 (q, J = 6 Hz 1 H , -CHCH3), 7.5 (m, 3 H, aromatic), 7.9 (m, 1 H , aromatic). 2-Allyl-3-methylphthalimidine:74%; bp 102-104 "C (0.15 mm); GLC homogeneous; ' H NMR (CDC13)6 1.45 (d, J = 6 Hz, 3 H , CHa), :3.6-6.:3 (overlapping signals, 6 H , allyl and >CHCH3), 7.5 (m, 3 H , aromatic), 7.9 (m. 1 H, aromatic). 2-(2-Chlorobenzyl)-3-methylphthalimidine:98%; bp 185 "C (0.05 m m ) ; ' H NMR ( C D C I ~6J 1.4 (d, J = 6 Hz, 3 H , CH3), 4.4 (q, J = 6 Hz. 1 H , >CHCH3), -1.55(d, J = 16 Hz, 1 H , benzylic), 5.25 (d, J = 16 Hz, 1 H. benzylic). '7.3 (m, 7 H. aromatic), 7.85 (m, 1 H, aromatic,. Method E. This method has been published; see ref 17. Isoindoles. Organolithium General Procedure. T o a stirred solution of the phthalimidine (25 mmol) in dry Et20 (150 mL) under nitrogen was added dropwise CHsLi (15 mL, 1.8 M in EtzO, 27 mmol). T h e mixture was stirred a t room temperature for 16 h, cooled, and treated with HzO (20 mL1. The E t 2 0 phase was separated, washed (H20).and dried IM~SO.,), keeping it ice-cold and under nitrogen as much as possible. The filtered extract was evaporated, and the residue was dried at 0.1 trim and protected from light. Isoindoles (Table 11). 1,2-DimethylisoindoleL2 (22,R = R' = CHa): from 2-methylphthalimidine and CH3Li; 78%; yellow-orange low-melting solid. 'H N N R (CDC18) 6 2.27 (s, 3 H , ArCH3), 3.47 (s, 3 H, >NCH,). 6-Chloro-1,3-dimethylisoindole(2,R = R' = CH3, R2 = H, X = 6-Cl): from 6-chloro-2-methylphthalimidine and CH3Li; 72%; oil; 'H NMR (CDC13) 6 2.3 ( s , 3H,ArCH3),3.6 ( s , 3H,>NCH3). 1,2,5-Trimethylisoindole(37):from 2,5-dimethylphthalimidine and CH3Li; 79%; oil; 'H NMR (CDC13) 6 2.3 (s, 3 H , ArCH3), 2.4 is, 3 H,ArCH:3),3.67 ( s , 3H , >NCH3). 1,2,6-Trimethylisoindole(32):from 2,6-dimethylphthalimidine and CHaL,i: 9l0/O;1.ellow-orange powder; 'H NMR (CDC13) 6 2.33 (s, 6 H , ArCH3), 3.53 (s, 3 H , >NCH3). 2-Benzyl-I-methylisoindole(2,R = CH&&, R L= CHI, R2 = X = H): from 2-xnzylphthalimidine and CH3Li; 98%; 'H NMR (CDCl,3)8 2.03 is. 3 H, ArCH?), 5.05 (s, 2 H, >NCHZAr). l-Ethyl-2-methyli~oindole~~ (2,R = CH3, R L= CzHj, R2 = X = H): from 2-methylphthalimidine and CZH5Li; 95%; oil; 'H NMR (CDCl?)8 1.12 ( t , 3 H, J = 7 Hz, -CHzCH3), 2.83 (9, 2 H , J = 7 Hz, -CH?CH:j), 3.53 ( s , , 3 H , :>NCH,). 2-Ethyl-1-methylisoindole(2, R = CzH5, R' = CH3, R2 = X = €I): from 2-ethylphthalimidine and CH3Li; 95%; oil. 5,6-Dichloro-1,2-dimethylisoindole(25): from 5,6-dichloro-2methylphthalimidine (24)and CH3Li: crude product, containing unreacted phthalimidine. was used directly in cycloaddition with benzyne. 6-Amino-1,2-dimethylisoindole (2,R = R' = CH3, R2 = H, X = 6-NH2): from 6-atni11o-2-rnethylphthalimidine~~ and CH3Li; crude yield 53%; mp i6-E7 OC; 'H XMR (CDC13) 6 2.30 (3 H , s, ArCHs), 3.30 ( 2 H, broad, exchangeable. -NHz), 3.57 (3 H , s, NCH3). Isoindoles (Tables 111-V). 2-Benzyl-1,3-dimethylisoindole: from 2-benzyl-3-rqethylphthalimidineand CH3Li; 97%; solid; 'H NMR (CDC13) 6 2 43 (s, 6 H, C H d , 5.33 (s, 2 H, benzylic). 2-Ethyl-1,3-dimethylisoindole:from 2-ethyl-3-methylphthalimidine and CHzL.; 94%: oil: 'H NMR (CDC13) 6 1.27 (t, J = 7 Hz, 3 H , --CH2CH:3).2 . i 7 is. 6 H , ArCH,), 4.03 (4, J = 7 Hz, 2 H , -CH2CH:
